Is (R)-ketamine a Potential Therapeutic Agent for Treatment-Resistant Depression with Less Detrimental Side Effects? A Review of Molecular Mechanisms Underlying Ketamine and its Enantiomers.

Summary

About one-third of people with major depressive disorder do not respond to standard antidepressants, and even those who do respond may wait weeks for effects. Ketamine, a mixture of two enantiomers, (R)-ketamine and (S)-ketamine, blocks NMDARs and shows rapid antidepressant effects in treatment-resistant depression. Preclinical evidence indicates (R)-ketamine has lower NMDAR affinity but greater and longer-lasting antidepressant potency with fewer side effects than racemic ketamine or (S)-ketamine. Ketamine and its enantiomers also modulate synaptogenesis and neurotransmission. This review summarizes current evidence on neurotransmission, neuroplasticity, and neural network activity as mechanisms, highlighting intracellular signaling pathways involving mTOR, ERK, and BDNF, and discusses probable mechanisms behind side effects.

Study at a glance

Abstract

Approximately one-third of individuals with major depressive disorder are resistant to conventional antidepressants (i.e., monoamine-based therapies), and, even among respondents, a proper therapeutic effect may require weeks of treatment. Ketamine, a racemic mixture of the two enantiomers, (R)-ketamine and (S)-ketamine, is an N-methyl-d-aspartate receptor (NMDAR) antagonist and has been shown to have rapid-acting antidepressant properties in patients with treatment-resistant depression (TRD). Although (R)-ketamine has a lower affinity for NMDAR, it presents greater potency and longer-lasting antidepressant properties, with no major side effects, than racemic ketamine or (S)-ketamine in preclinical findings. Thereby, ketamine and its enantiomers have not only an antagonistic effect on NMDAR but also a strong synaptogenic-modulatory effect, which is impaired in TRD pathophysiology. In this review, we summarize the current evidence regarding the modulation of neurotransmission, neuroplasticity, and neural network activity as putative mechanisms of these rapid-acting antidepressants, highlighting differences on intracellular signaling pathways of synaptic proteins such as mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and brain-derived neurotrophic factor (BDNF). In addition, we discuss probable mechanisms involved in the side effects of ketamine and its enantiomers.